Radiotherapy-induced fatigue (RIF) is the hallmark symptom of irradiated cancer patients with a prevalence as high as 78-100%. The development of RIF is most likely related to a combination of mitochondrial dysfunction, changes in skeletal muscle structure and function, a systemic pro-inflammatory response, alterations in the central nervous system and neuroendocrine dysregulations. The link between objective multi-system genomic, transcriptional, inflammatory and hormonal changes and subjective symptom experiences of RIF is not well understood. Our theoretical model suggests that one mechanism for RIF is a cancer-induced mitochondrial dysfunction, which is further aggravated by radiation treatment. Together, these events result in energy depletion, muscle and central nervous system dysfunction, local and systemic inflammatory responses which have been associated with symptoms including fatigue, mood and sleep disturbances. This proposed descriptive molecular study is based on collaboration between the University of Rochester (UR) and the University of Washington (UW). A larger (N=122) prospective, randomized, 2-arm, controlled study is being conducted at the UR with prostate cancer patients undergoing radiation treatment (PC061518 "The Influence of Home-Based Aerobic and Resistance Exercise on Cancer-Related Fatigue, Strength, and Muscle Mass in Prostate Patients During Radiotherapy"). In this application we propose to describe discrete differences in nuclear and mitochondrial gene expression using a human mitochondrial gene expression gene chip (huMITOchip) at three parent trial time points (baseline, after radiation treatment alone, after radiation + exercise). In addition, the relationship of nuclear and mitochondrial gene expression to changes in patient- reported fatigue alone will be explored. At the UR (parent trial), repeated skeletal muscle biopsies (vastus lateralis) will be collected before (n=40) and after (n=40) an exercise intervention program in prostate cancer patients receiving 6 weeks of radiation treatment. At the UW (current proposed project) the nuclear and mitochondrial-relevant gene expression changes in skeletal muscle will be examined with a novel, proprietary mitochondrial-focused oligonucleotide microarray (huMITOchip) developed by the principal investigator. The huMITOchip will enable us to determine changes in nuclear genes related to muscle function, lipid metabolism and inflammation and nuclear and mitochondrial genes of four major mitochondrial pathways (electron transport chain, oxidative phosphorylation, ATP production, and apoptosis) that we hypothesize are associated with a RIF. The results will generate sufficient pilot data to further examine the relationships between cellular alterations and symptom experiences, mechanisms (e.g., inflammatory changes) that account for symptom reports, as well as additional strategies to improve quality of life in cancer patients undergoing radiation treatment. Our interdisciplinary team is uniquely suited to conduct the proposed study, because of our prior work, the supportive research environments including the UW microarray core facility, and the opportunity to access a patient population currently enrolled in a Department of Defense funded study at UR. PUBLIC HEALTH RELEVANCE: The proposed descriptive study is based on a collaboration between the University of Rochester (UR) and the University of Washington (UW). A larger (N=122) prospective randomized, 2-arm, controlled intervention study will be conducted at the UR with prostate cancer patients undergoing radiation treatment (parent project). As part of the parent trial, consecutive patients will be recruited into the proposed pilot study in which repeated muscle biopsies before (n=40) and after (n=40) radiation treatment and/ randomized into an exercise intervention program will be obtained. The parent trial will also collect self-report fatigue data at baseline and at the end of treatment in both groups. Gene expression studies will be conducted by the PI at the UW.